The long range objective of this research proposal is to study the hepatic process of gluconeogenesis in vivo, that is, in the dog and ultimately in intact man. Specifically, we wish to: 1) determine the contribution of circulating alanine to hepatic glucose production in the fed, postabsorptive, and prolonged fasted states; 2) define the physiological roles of insulin and glucagon in the regulation of gluconeogenesis from alanine; and 3) study the pathophysiology of the accelerated gluconeogenesis of diabetic man. In addition, we are investigating the roles of insulin and glucagon in the regulation of total hepatic glucose production which is derived from glycogenolysis as well as gluconeogenesis. To date, our studies have involed the first two objectives. In normal man, using the hepatic vein catheterization technique combined with a constant infusion of alanine-14C, we have examined the effects of fasting 12 and 48 hours and 3 weeks. Using somatostatin, we have also examined the roles of basal insulin and glucagon in regulating basal gluconeogenesis and glucose production in the dog and glucose production in intact man. We have also noted that sustained elevations of circulating glucagon result in only transient stimulation of hepatic glucose production. In the next year we plan to examine the roles of insulin and glucagon in intact man in regulating gluconeogenesis from alanine. We will use somatostatin as a means of producing isolated deficiencies of insulin and glucagon. We will also examine the role of glucose (independent of insulin) in regulating gluconeogenesis and glucose production. BIBLIOGRAPHIC REFERENCES: Liljenquist, J.E., G.L. Mueller, A.D. Cherrington, U. Keller, J.L. Chiasson, J.M. Perry, W.W. Lacy, and D. Rabinowitz. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J. Clin. Invest. 59:369-374, 1977. Chiasson, J.L., J.E. Liljenquist, W.W. Lacy, A.S. Jennings and A.D. Cherrington. Gluconeogenesis: Methodological approaches in vivo. Federation Proc. 36:229-235, 1977.